In response to both pathological and physiologic stimulation the adult myocardium can hypertrophy as a means of adapting cardiac output following injury or in response to alterations in demand. While cardiac pathologic hypertrophy can initially be a compensatory response that temporarily augments function, prolongation of this state can be deleterious and eventually leads to heart failure and/or sudden death. Cardiac hypertrophy results from molecular reprogramming in gene expression, protein stability and turnover, RNA stability and content, metabolism, and composition of the extracellular matrix. Many of these processes are mediated by signal transduction pathways that directly modify intracellular regulatory proteins through phosphorylation or dephosphorylation. The current application will examine the ERK1/2 branch of the MARK signaling pathway to definitively address its functional role and relevance in mediating the hypertrophic response in vivo. While countless of studies have evaluated the importance of ERK1/2 MARK signaling in cardiac myocyte cultures, it is important to note that almost nothing has been reported in vivo as to the necessary and sufficient functions of MEK1-ERK1/2 signaling within the adult heart. Thus, this "central" kinase that responds to nearly all cardiac stress stimuli, has yet to be definitively evaluated in vivo. Here we will examine the overarching hypothesis that ERK1/2 signaling is a necessary and sufficient event in mediating physiologic and pathophysiologic cardiac hypertrophy in vivo. To address this hypothesis three specific aims are proposed. Aim 1 will employ two distinct loss-of-function approaches in genetically modified mice to evaluate the necessity of ERK1/2 as hypertrophic mediators. Aim 2 will evaluate the importance of the dual specificity phosphatases as ERK1/2 inactivating factors using novel gene-targeted mice, which will determine the sufficiency of ERK1/2 in regulating hypertrophy. Aim 3 will evaluate the downstream molecular mechanisms whereby ERK1/2 program cardiac hypertrophy and other aspects of the cardiac stress response. If MEK1-ERK1/2 are determined to truly function as "focal" kinases underlying the cardiac hypertrophic response, they may be attractive targets for therapeutic strategies in humans.